1. Field of the Invention
The invention in the field of biochemistry and medicine relates to methods to kill melanoma cells and treat melanoma tumors in a selective manner using compositions that inhibit the mitogen-activated protein kinase (MAPK) pathway.
2. Description of the Background Art
The MAPK pathways are found in, and highly conserved among, all eukaryotes. These pathways play an integral role in the transduction of various extracellular signals into the nucleus. The best-characterized mammalian pathway, designated Raf-MEK1/2-ERK1/2, includes the MAPK enzymes also known as ERK1 and ERK2, which are phosphorylated and activated by the dual-specificity kinases that have been termed “MAPK/ERK kinases” (abbreviated variously as MAPKK1 and MAPKK2 or, as will be used herein, MEK1 and MEK2). The MEK enzymes are in turn phosphorylated and activated by the Raf kinases (Lewis, TS. et al., Adv Canc Res, 74:49-139 (1998)).
The MAPK pathway is involved in the regulation of cell growth, survival, and differentiation (Lewis et al., supra). Furthermore, activated MAPK and/or elevated level of MAPK expression have been detected in a variety of human tumors (Hoshino, R. et al., Oncogene 18:813-822 (1999); Salh, B et al., Anticancer Res. 19:741-48 (1999); Sivaraman, V S et al., J. Clin. Invest. 99:1478-483 (1997); Mandell, J W et al., Am. J. Pathol. 153:1411-23 (1998); Licato, L. L. et al. Digestive Diseases and Sciences 43, 1454-1464 (1998)) and may be associated with invasive, metastatic and angiogenic activities of tumor cells. Thus, inappropriate activation of the MAPK pathway is an essential feature common to many types of tumors. For this reason, participants in this signaling pathway, such as MEK, are potential targets for cancer therapy.
However, it has generally been observed that inhibitors of signal transduction, including of the MAPK pathway, are cytostatic in nature, merely arresting the growth of tumor cells but not killing them,. creating an expectation that non-traditional approaches would be required to develop such agents into clinical therapeutics.
The present inventors and their colleagues observed in the National Cancer Institute's Antineoplastic Drug Screen (NCI-ADS) database (Koo, H.-M. et al., Canc Res 56:5211-5216 (1996); Monks, A. et al. J Natl Canc Inst 83:757-766 (1991); Grever, M. R. et al., Sem Oncol 19:622-638 (1992)) that the lethal factor (LF) of Bacillus anthracis, a MEK-directed protease (Duesbery, N. S. et al., Science 280:734-737 (1998); Vitale, G. et al., Biochem Biophys Res Comm 248:706-711-(1998)) and the small molecule pharmacological MEK inhibitor PD98059 (Dudley, D. T. et al., Proc Nat'l Acad Sci USA 92:7686-7689 (1995); Alessi, D. R. et al., J Biol Chem 270:27489-27494 (1995)) displayed enhanced growth inhibition specifically against melanoma lines among the many different tumor cell lines tested. Another small molecule MEK inhibitor, PD184352, has been described (Sebolt-Leopold, J S et al., Nature Med. 5: 810-816 (1999)).
The present invention is based on subsequent work wherein the inventors explored the mechanism by which inhibition of the MAPK signaling would selectively inhibit the growth of the human melanoma cells.
The incidence of malignant melanoma is increasing dramatically in all parts of the world (Parker, S. et al., CA Cancer J Clin 47:5-27 (1997)). The estimated lifetime risk for the population with light-colored skin is reaching 1 in 75 by the year 2000. Melanoma can be one of the most aggressive malignancies as the tumor readily metastasizes early in disease progression. Early detection and surgical intervention remain the mainstays of treatment for localized melanoma. Despite improved diagnosis and characterization, long-term survival from the advanced disease has not improved.
The present inventors' observation that inhibition of MAPK signaling specifically triggers an apoptotic response in human melanoma cells, but not in normal melanocytes or in other cell types, provides a novel, selective therapeutic strategy for systematic treatment of malignant melanomas.
Citation of the above documents is not intended as an admission that any of the foregoing is pertinent prior art. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicant and does not constitute any admission as to the correctness of the dates or contents of these documents.